The regulation of estrogen receptor activity and metabolism is being investigated in vitro in MCF-7 human breast cancer cells, and in normal hamster uteri in vivo and in vitro. The enhancement of estrogen receptor activity by melatonin, and its dependence upon protein synthesis, is being studied in whole cell and cell-free systems to determine the mechanism of this regulation. The physiochemical changes and alterations in biological activity of the receptor induced in these cells by melatonin are being characterized using analytical biochemical techniques. Structural differences between estrogen receptors of normal and malignant tissues, and their modification by melatonin, are being studied to better understand the treatment and response of women with hormone-dependent breast cancer. The 24-hour plasma melatonin profiles, plasma steroid hormone levels, and hormonal and familial risk factors have been studied in women with breast cancer, in women at high risk for breast cancer, and in normal subjects. In women with breast cancer the relationship of plasma melatonin to the estrogen and progesterone receptor content of the primary tumor, hormonal risk factors, and extent of disease has been established. Women with hormonal dependent breast cancer have a depression of their plasma melatonin which is independent of all other parameters studied. This abnormality is also present in women at high risk for breast cancer but not found in normal subjects. The possibility of plasma melatonin being an etiologic factor for determining the presence or absence of hormone-dependent breast cancer is being studied in these subjects.